Credit: SOURCE: EUROPEAN SOCIETY OF CLINICAL MICROBIOLOGY AND INFECTIOUS DISEASES

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Who has not dreamed of a cure for the common cold? It might be a pill that banishes the sniffles, to be taken as soon as you notice the symptoms. Or better yet, a vaccine administered before kindergarten, along with those for measles and mumps. Imagine a world without colds—without weeks of wet Kleenex and phlegmy avalanches in your sinuses. It sounds pretty perfect.

Scientists, in fact, are working toward a vaccine against rhinoviruses—the group that causes 30 to 50 percent of colds. But, ironically, even if it succeeds or if drugs that stop colds in their tracks are found, we may well decide that most of us are better off without these wonder drugs, after all.

Goodness knows our dreams of becoming sniffles-free have been dashed before. Take the case of the anticold drug pleconaril, which received sensational media coverage in 2002 while it was still in clinical trials. Heralded as “the miracle drug,” “the magic bullet” and “the Holy Grail,” it performed well in cell culture, but its effects in human subjects were not very impressive—it shortened colds by one day. What prompted the U.S. Food and Drug Administration to reject pleconaril, however, were the side effects. It caused some women to bleed between menstrual periods and interfered with hormonal birth control. Indeed, two women in a trial became pregnant while taking it. Numerous other candidates have been abandoned owing to their adverse effects, including nasal inflammation worse than the infection. The common cold, it turns out, is not that bad, compared with some treatments.

Much effort has also gone into vaccines, particularly against rhinoviruses. (Colds are also caused by adenoviruses, coronaviruses and other virus families.) Like HIV, a rhinovirus consists of an RNA genome cocooned in a shell of proteins called a capsid. The virus attaches to the membrane of a host cell, injects its genetic material and then hijacks the host’s machinery to make more of itself. It is the body’s own inflammatory immune response, not viral replication itself, that causes symptoms.

In searching for vaccine candidates against rhinovirus, researchers have concentrated on looking for some piece of the capsid that is the same across all types. A vaccine containing that piece, when given to a healthy person, should, in theory, cause the immune system to produce antibodies against it so that he or she is primed to fend off a later infection by all viral strains bearing that piece. The goal is to pick a shared fragment that does not change much over time; the best vaccines and drugs can be rendered useless by a significant alteration in a target.

For years researchers met disappointment after disappointment in their efforts to find a conserved element in rhinoviruses. Examination of more than 100 variants of the virus had turned up no commonality, says Thomas J. Smith, who studies the structure of the virus at the Donald Danforth Plant Science Center in St. Louis. This variability occurs because, as an RNA virus, a rhinovirus is prone to mutations. The enzymes that replicate RNA do not have any of the proofreading mechanisms possessed by the enzymes that replicate DNA, so each new virus may be peppered with changes in its code, and each type can drift considerably from the others in its capsid makeup. In contrast, a vaccine has been developed against adenovirus, which is a DNA virus—although its use has been restricted to military personnel.

About 10 years ago, though, to Smith’s surprise, he found that parts of the rhinovirus that researchers thought were buried—and thus out of view of the immune system—actually appeared on the surface, at least some of the time. He and his colleagues eventually concluded that the capsid might be more dynamic than previously thought, shifting and exposing hidden regions. They called the process “breathing.”

As it turns out, one of these pieces, a protein called VP4 that helps the virus attach to the cell, is very similar across nearly all rhinoviruses. It had been overlooked because it was exposed only sometimes on the outside of the capsid.

Preliminary research in cell cultures done by Smith’s team in 2009 demonstrated that a VP4-type vaccine conferred immunity to three strains of rhinoviruses, suggesting that a vaccine of that kind might be useful for protecting against many colds. But the prospect is far from a sure thing. “I’m not going to oversell it,” Smith remarks. It turns out that VP4 is not normally prominent enough to provoke a serious response. To use a protein like VP4 in a vaccine, he says, you would have to somehow convince the immune system to go after it.

An idea put forth two years ago by Gregory Tobin of Biological Mimetics in Frederick, Md., may offer a way around this difficulty. Tobin and his colleagues suggested that delivering large amounts of a protein not normally recognized by the immune system might evoke a protective immune response. This strategy has shown some encouraging signs in early work with foot-and-mouth disease and is being investigated for HIV, but the strategy is not yet proven.

As for drugs that might act once a cold sets in, the pitfalls of pleconaril still await. “The infection won’t kill you, so the treatment has to be safe as water,” Smith says. Ronald B. Turner, a cold virus researcher at University of Virginia, echoes that thought: “It has to be very effective, it has to be absolutely cheap, and it has to be completely safe.” The bar is thus set very high. Even after more than 50 years of work on the rhinovirus, not a single drug that targets it is on the market.

Although few drug companies are working on the common cold anymore, some are still taking aim at rhinoviruses. Over the past few decades research has implicated the viruses in serious complications of asthma, emphysema and cystic fibrosis. “From a drug discovery perspective, if you have efficacy for a more severe illness, the risk that your drug is going to wash out based on toxicity, safety and cost issues becomes less,” Turner says.

Targeting closely related groups of rhinoviruses offers one direction for treatment. In 2009 Stephen B. Liggett of the University of Maryland and his colleagues published the complete genomes of 109 rhinoviruses, including an evolutionary tree depicting their relationships. “If you could look at that tree and draw a circle around a group of viruses that cause a really powerful exacerbation of asthma, you could target those [viruses] directly,” Liggett says. And closely related viruses might respond more consistently to a treatment than hundreds of more diverse viruses do.

In the end, it may not be the worst thing that rhinoviruses have so cleverly evaded our grasp. Some research suggests that colds may provide temporary immunity to more severe infections. For example, the 2009 pandemic H1N1 flu did not spread in earnest in France until after the cold season was over. Jean-Sebastien Casalegno of the French National Influenza Center reports that colds among children appeared to reduce the likelihood of infection with H1N1, although he emphasizes that the connection is still just a hypothesis. “If we completely succeed in eliminating all rhinovirus infections, other respiratory viruses, such as influenza, may move into that niche,” he speculates.

It is possible that virus-fighting cold treatments in the future would not eliminate infection but might still make you feel better. Turner points out that a third of all rhinovirus infections do not produce cold symptoms. “Clearly, the inflammatory response isn’t necessary for elimination of the virus, because those people get over their infections just like everybody else,” he says. To that end, future treatments might tamp down the immune response or reduce the amount of virus in the body just enough to elude symptoms. But as with all the potential cold cures, there is a caveat—would we want to impede our immune systems? In so doing, we might trade a minor nuisance for ailments or side effects that are even more severe. That, unfortunately, is the inescapable, central conundrum of curing the cold: the cure may be worse than the inconvenience.

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